The main goal of this Project is to investigate mechanisms that define the transition from healthy aging to mild cognitive impairment and to mild Alzheimer's disease (AD) using structural imaging techniques. Such techniques allow the in vivo measurement of structural changes in the brain that are surrogate markers of the ongoing pathological changes associated with AD. In addition, such techniques make it possible to: a) relate alterations in given brain regions to cognitive decline, and b) examine the specific role of certain brain structures in human memory function because of the age- or disease-related occurrence of lesions in these structures. The Project uses a longitudinal design with yearly MRI scans and clinical evaluations. Because of the opportunities that a longitudinal design affords, an additional goal of the Project is to develop sensitive MRI risk factors of incident dementia. Since pathology in given brain regions probably occurs many years prior to the clinical manifestations of AD, such markers are important for differentiating individuals at risk from healthy elderly people so that possible interventional strategies can be targeted early. An important feature of the application is the use of diffusion tensor imaging (DTI) to define and quantify deterioration of white matter as a function of age and disease progression. This is a structural imaging technique that can detect alterations in the microstructure of normal appearing white matter. A novel feature of this application is the use of high resolution DTI to define and quantify pathology in the angular bundle that includes the perforant path, in order to distinguish those at risk of developing AD. In addition to volumetric measures of regions of interest, whole brain voxel based morphometry will be used to delineate patterns of change that define the transition from healthy aging to MCI and from MCI to mild AD. Summary of the Project 1 Discussion: The overall discussion of the Project emphasized the positive aspects of the well-characterized group of individuals and the yearly follow-up. Despite some concerns about the Regions of Interest (ROI) approach raised by some reviewers, a general consensus formed that the ROI approach remains an excellent research tool. It was noted that, while the ongoing work is limited by subject sample size, it is focused on novel biological hypotheses that will extend current knowledge about transition states from normal aging to AD and is therefore quite relevant. Concerns, however, remain regarding the focus on AD as the sole process by which individuals transition from normal aging to mild cognitive impairment and then on to dementia. There was general agreement that there may be different mechanisms by which individuals could transition from normal aging to mild cognitive impairment. For example, cerebrovascular disease is common amongst older individuals and would likely contribute to such changes. In fact, one reviewer pointed to the fact that the Project has the ability to examine this question directly (e.g. relevant clinical information and imaging) and should do so. Finally, it was noted that there remained some question of integration between Project 1 and Project 2. It was unclear the extent to which the projects shared subjects and, if so, how this was done. In conclusion, the reviewers felt that overall the Project was very good to excellent, but that some conceptual and methodological issues still remained.